Mechanisms of STING-Mediated Mucosal Vaccine Adjuvant Activity of Cyclic di-GMP

STING 介导的环二 GMP 粘膜疫苗佐剂活性机制

• 批准号: 9185213
• 负责人: LEI JIN
• 金额: $ 29.86万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185213
• 关键词: Adjuvant; Adopted; Advanced Development; Antibody Formation; Antigens; Attenuated; CD8B1 gene; Cells; Data; Dendritic Cells; Development; Effector Cell; Exhibits; Future; Gene Expression; Genes; Goals; Human; ITGAM gene; IgG1; Immune response; Immunity; Immunization; Immunoglobulin A; Infection; Infectious Agent; Inflammatory; Influenza A Virus, H5N1 Subtype; Interferons; Knowledge; Lead; Lung; Lymphoid Tissue; Mediating; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mus; Nose; Periodicity; Play; Production; Proteins; Publishing; Research; Role; Route; Safety; Signal Transduction; Streptococcus pneumoniae; Surface; T cell response; TNF gene; TNFRSF1A gene; TNFRSF1B gene; Vaccine Adjuvant; Vaccines; base; cytokine; immunogenic; immunogenicity; improved; in vivo; macrophage; migration; mucosal vaccination; mucosal vaccine; pathogen; pneumococcal surface protein A; public health relevance; receptor; response; vaccine development

DESCRIPTION (provided by applicant): The goal of this proposal is to uncover the in vivo mechanisms by which STING (Stimulator of interferon genes) mediates the mucosal vaccine adjuvant activity of cyclic di-GMP (CDG). Protective mucosal immune responses are most effectively induced by mucosal immunization. However, most of the currently approved human vaccines are administered systemically and generally fail to elicit effective mucosal immunity. Live attenuated mucosal vaccines present safety and acceptability issues while purified antigens are generally poor immunogenic when administered by the mucosal route. CDG exhibits potent mucosal immunogenicity thus, has been explored as a promising mucosal vaccine adjuvant. The mechanism by which CDG executes its mucosal adjuvant activity is unknown, which hinders the further development of CDG as an efficacious mucosal adjuvant. STING, also known as MPYS/MITA, is a receptor for CDG. We recently showed that STING-/- mice fail to generate Ag-specific antibody production or TH1-TH2-TH17 T cell response after intranasal CDG/Ag immunization. We further discovered that STING-dependent TNF-a is essential for CDG adjuvant activity in vivo. Intranasal co-administration of CDG/Ag induces immune response in lung and nasal-associated lymphoid tissue (NALT). Here, we will use TNFR1-/-TNFR2-/- and conditional STING-/- mice to dissect the in vivo mechanism of CDG/STING-induced adjuvant activity in lung and NALT. We will adopt both the model Ag OVA and pneumococcal surface protein A (PspA) Ag for our study. Dendritic cells (DC) play a central role in adjuvant activity. We hypothesize that CDG induces STING-dependent inflammatory signals that activate DC directly or indirectly to execute the adjuvant activity of CDG. Two specific Aims are proposed to carry out this objective. Aim 1. Determine how STING regulates CDG-induced adjuvant activity in DC. Aim 2. Determine how TNF-a regulates CDG-induced adjuvant activity. Currently, there is no vaccine formulation containing a mucosal adjuvant approved for human use. The knowledge generated by our studies can help advance the development of CDG as an efficacious mucosal vaccine adjuvant for human use.

描述（由申请人提供）：该提案的目的是揭示刺痛（干扰素基因刺激剂）介导环状DI-GMP（CDG）的粘膜疫苗辅助活性的体内机制。保护性粘膜免疫反应最有效地由粘膜免疫诱导。但是，大多数当前批准的人类疫苗是系统地施用的，通常无法引起有效的粘膜免疫。通过粘膜途径给药，纯化的抗原的活粘膜疫苗在粘膜疫苗中的免疫原性通常不良。因此，CDG表现出有效的粘膜免疫原性，已被探讨为有希望的粘膜疫苗辅助。 CDG执行其粘膜辅助活性的机制尚不清楚，这阻碍了CDG作为有效的粘膜佐剂的进一步发展。 Sting，也称为MPYS/MITA，是CDG的受体。我们最近表明，在鼻内CDG/Ag免疫后，STING - / - 小鼠无法产生Ag特异性抗体产生或Th1-Th2-Th17 T细胞反应。我们进一步发现，依赖于STING的TNF-A对于体内CDG辅助活性至关重要。 CDG/Ag的鼻内共同给药可诱导肺和鼻相关淋巴组织（NALT）中的免疫反应。在这里，我们将使用TNFR1 - / - TNFR2 - / - 和条件刺痛 - / - 小鼠在肺和NALT中剖析CDG/STING诱导的辅助活性的体内机理。我们将同时采用模型Ag OVA和肺炎球菌表面蛋白A（PSPA）Ag进行研究。树突状细胞（DC）在辅助活性中起着核心作用。我们假设CDG诱导依赖刺激性的炎症信号，该信号直接或间接激活DC以执行CDG的辅助活性。提出了两个具体的目标来实现这一目标。 AIM 1。确定STIN如何调节DC中CDG诱导的辅助活性。目标2。确定TNF-A如何调节CDG诱导的辅助活性。当前，尚无疫苗配方，其中包含批准用于人类使用的粘膜佐剂。我们的研究产生的知识可以帮助推进CDG作为人类使用的有效粘膜疫苗辅助。